The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-kB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient-derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion.
The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3þ3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m 2 once weekly every 3 of 4 weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m 2 was determined to be the MTD. At 63 mg/m 2 , dose-limiting toxicities included headache, nausea, and vomiting. Two cases of Bell's palsy (grade 2) also occurred at 63 mg/m 2
Background and Purpose. The cost of illness in cancer care and the subsequent distress has attracted scrutiny. Guidelines recommend enhanced discussion of costs, assuming this will reduce both stress and costs. Little is known about patient attitudes about cost considerations influencing treatment decisions. Methods. A convenience-sample survey of patients currently receiving radiation and/or intravenous chemotherapy at an outpatient cancer center was performed. Assessments included prevalence and extent of financial burden, level of financial distress, attitudes about using costs to influence treatment decisions, and frequency or desirability of cost discussions with oncologists. Results. A total of 132 participants (94%) responded. Overall, 47% reported high financial stress, 30.8% felt well informed about costs prior to treatment, and 71% rarely spoke to their
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